Marijuana components, such as delta-9-tetrahydrocannibinol, alter immune functions. Cannabinoids are known to affect cytokine production and to alter cells and humoral immunity. Newly discovered endogenous cannabinoids have also be found to affect similar immune function. However, the mechanism by which cannabinoids have also been found to affect similar immune functions. However, the mechanism by which exogenous or endogenous cannabinoids modulate these immune factors is unknown. Recently, two cannabinoid receptors were cloned, the central cannabinoid receptor (CB1 receptor) and the peripheral cannabinoid receptor (CB2 receptor). The CB1 receptor is expressed predominantly in the central nervous system. The CB2 receptor is expressed pred9ominantly in cells of the immune system, suggesting that this receptor is involved in immunoregulatory events. However, the role of the endogenous cannabinoid system in the immune system remains unknown. The specific objective of this research proposal is to investigate the role of endogenous CB2 receptor activation on cell and humoral immunity. Cannabinoids are known to inhibit the activity of Th1 cells (cells involved in cell mediated immunity), and to enhance the activity of Th2 cells (cells involved in humoral activity). To determine whether the CB2 plays a role in differentially activating the Th1/Th2 cell populations, cells derived from a unique animal model will be used. This mouse model is the CB2 knockout mouse (CB2 ko mouse) which is deficient for the CB2 receptor. Th1/Th2 cell activation will then determined in CB2 ko and wild type mice splenocytes by measuring the Th1- and Th2-specific cytokines, interferon gamma (INFgamma) and interleukin-4 (IL-4), respectively. INFgamma and IL-4 will be measured by enzyme-linked immunoassay. Furthermore, since Th2 cells are involved in humoral response, antibody production will be measured in antigen challenged CB2 ko and wild type mice cells. Understanding the endogenous role of the cannabinoid system in the immune system will be clinically useful, since it will enable the educated use of cannabinoids to alter specific immune functions without having any unwanted CNS side effects.